title: Microsatellite instability due to hMLH1 deficiency is associated with increased cytotoxicity to irinotecan in human colorectal cancer cell lines.
abstract: Around 15% of colorectal cancers (CRCs) show microsatellite instability (MSI) due to dysfunction of the mismatch repair system (MMR). As a consequence of this, MSI tumours tend to accumulate errors in mononucleotide repeats as those in genes implicated in repairing double-strand breaks (DSBs). Previous studies have shown that irinotecan (CPT-11), a chemotherapy agent inducing DSB, is more active in MSI than in microsatellite stable (MSS) CRC. The purpose of this study was to compare the sensitivity to CPT-11 in a series of CRC cell lines with either proficient or deficient MMR and to assess the mutational status of two DSB repair genes, MRE11 and RAD50, in these cell lines. hMLH1-deficient cell lines due to either epigenetic silencing or mutation showed very similar IC(50) and were four- to nine-fold more sensitive to CPT-11 than the MSS line. Cell lines harbouring mutations in both MRE11 and RAD50 were most sensitive to CPT-11. We conclude that MSI cell lines display higher sensitivity to CPT-11 than MSS cells. Mutation of MRE11 and RAD50 could account for this difference in response to CPT-11. Future clinical trials tailoring chemotherapy regimens based on microsatellite status are warranted.
authors.affiliation: Department of Medical Oncology and Laboratory of Oncology Research, Vall d'Hebron University Hospital, Barcelona, Spain. evilar@umich.edu
authors.forename: E
authors.initials: E
authors.lastname: Vilar
authors.forename: M
authors.initials: M
authors.lastname: Scaltriti
authors.forename: J
authors.initials: J
authors.lastname: Balmaña
authors.forename: C
authors.initials: C
authors.lastname: Saura
authors.forename: M
authors.initials: M
authors.lastname: Guzman
authors.forename: J
authors.initials: J
authors.lastname: Arribas
authors.forename: J
authors.initials: J
authors.lastname: Baselga
authors.forename: J
authors.initials: J
authors.lastname: Tabernero
mesh_terms: D017766:Acid Anhydride Hydrolases; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology; D045744:Cell Line, Tumor / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D003603:Cytotoxins / Q000494:pharmacology; D045643:DNA Repair Enzymes / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics; D006801:Humans; D000077146:Irinotecan; D000076228:MRE11 Homologue Protein; D053842:Microsatellite Instability; D000070957:MutL Protein Homolog 1; D009687:Nuclear Proteins / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000972:Antineoplastic Agents, Phytogenic; D003603:Cytotoxins; D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; C501486:MLH1 protein, human; C121766:MRE11 protein, human; D009687:Nuclear Proteins; D000077146:Irinotecan; D000076228:MRE11 Homologue Protein; D017766:Acid Anhydride Hydrolases; C112158:RAD50 protein, human; D000070957:MutL Protein Homolog 1; D045643:DNA Repair Enzymes; D002166:Camptothecin